16alpha,17alpha-ethylene and substituted ethylene pregnane derivatives and process



United States Patent (Mike ABSTRACT OF THE DISCLOSURE New16a,l7a-ethylene and 160:,17oc-SllbSiliUt6d ethylene derivatives of thepregnane series prepared by the photochemical reaction of an olefin orsubstituted olefin with a A -ene of the pregnane series useful asanti-inflammatory agents.

This invention relates to novel cyclopentanophenanthrene derivatives andto a process for the production thereof. More specifically thisinvention relates to novel 16a,17a-ethylene and 16a,17u-substitutedethylene derivatives of the pregnane series.

The compounds of the present invention may be represented by thefollowing structural formula:

T zR (1:0 a? Rzufij "(ll-B Z 1 wherein Z is a carbon-carbon single bond,a carbon-carbon double bond or the group "oXY bridging the C-1 and C-2carbon atoms, wherein each of X and Y is hydrogen, chloro or fluoro;

Z is a carbon-carbon single bond, a carbon-carbon double bond or thegroup methyl, R being in the is the group and R being in either the a orfi-configuration when Z is a carbon-carbon single bond;

R is hydrogen, fl-hydroxy, keto or B-chloro;

R is hydrogen, fluoro or chloro, R and R being the same when R ishydrogen or chloro;

R is an oxygen atom or the group 3,435,057 Patented Mar. 25, 1969tetrahydropyranyl or a hydrogroup of less than 12 carbon in which R ishydrogen, carbon carboxylic acyl atoms;

each of A and B is hydrogen, chloro, fluoro or an alkyl group of from 1to 4 carbon atoms each of D and E is hydrogen, chloro, fiuoro, an alkylgroup of from 1 to 4 carbon atoms, an alkoxy group of from 1 to 4 carbonatoms or a haloalkyl group of from 1 to 4 carbon atoms, and

A and B taken together are methylene or difluoromethylene.

The compounds of the present invention demonstrate corticoid activityand are useful as anti-inflammatory agents in the treatment ofconditions usually responsive to such agents, such as rheumatoidarthritis, contact dermatitis, allergies and the like. These compoundsmay be administered via usual routes in the standard pharmaceuticalcompositions and at dosages appropriate for the particular conditionbeing treated.

The compounds of the present invention are prepared in accordance withthe following reaction scheme:

wherein each of Z and Z is a methylene or halomethylene group or acarbon-carbon single bond, R is hydroxy or hydrocarbon carboxylicacyloxy group; all other substitutents being as previously defined.

According to the foregoing transformation, a A -ene of Formula II and anolefin of the formula a wherein each of A, B, D and E is as previouslydefined, are irradiated with ultraviolet light of a wavelength in therange of about 270 to 330 mg in the presence of an inert organic solventsuch as benzene, dioxane and the like, preferably benzene. Under theseconditions, the olefin adds across the A -double bond with theorientation of the resulting substituted ethylene group with respect tothe carbon atoms at 16, 17 positions being predornninantly a.

While the time for this reaction will in part be dependent upon thereactivity of the reagents, a reaction time of a few hours, e.g., 4 to 5hours is generally adequate for ethylene and for substituted olefinswhose substituents contribute a positive inductive effect to the doublebond, such as alkyl. Longer periods for the reaction time e.g. up to 40or 50 hours may be required for those oleflns whose substituentscontribute a negative inductive effect to the double bond, such asfluoro, or chloro. In any event, the course of the reaction may bereadily followed through observation of the U.V. spectra of the reactionmixture.

In the practice of the process, a 3-keto-A -ene is preferably protectedby formation of an ethylene ketal as through the action ofZ-methyl-Z-ethyl-1,3-dioxolane and p-toluenesulfonic acid. When aprotecting group is not used, side products may be formed. The sideproducts can be separated, however, from the l6a,l7a-compounds bystandard procedures, e.g., chromatography.

The A -ene starting material for this conversion is generally readilyavailable or is conveniently prepared by dehydration with aceticanhydride and pyruvic acid of the bis-semicarbazone of the appropriate17a-hydroxy- 3,20-diketo compound.

Those starting materials of Formula II bearing a halomethylenesubstituent in the lulu-position and/ or 60:,711- position may beobtained by treatment of a A or A compound wth an alkali or alkalineearth metal salt of an acid having the formula WCXYCOOH in which W ischloro or iodo and X and Y are hydrogen, chloro or fluoro, at least oneof X and Y being other than hydrogen. leaflet-methylene and/or6a,'7a-methylene groups may be obtained through the reductivedehalogenation of the corresponding la, 2a, or 6a,7a-chloromethylenecompound with lithium aluminum hydride or, alternatively, through theaction of dimethylsulfoxonium methylide in dimethylsulfoxide on a Aand/or A dehydro intermediate.

In performing the process of the present invention, the substituentsrepresented by R R and R may be present in the starting material or maybe introduced subsequently by conventional techniques. In practice, R isgenerally hydrocarbon carboxylic acyloxy group, preferably acetoxy.

A 6-fluoro or chloro substituent may be introduced in the 3-keto-A -enesubsequent to olefin addition by initial formation of a 3-ethoxy-A-diene with ethyl orthoformate and fluorination of this intermediatewith perchloryl fluoride. Acid isomerization of the 6fi-fiuoro compoundaffords the 3-keto-6a-fluoro-A -ene. In a similar fashion, treatment ofthe enol ether with N-chlorosuccinimide, followed by acid isomerization,affords the 3-keto-6achloro-A -ene. When R is methyl, this substituentis preferably present in the starting material.

In practice, the 16a,17a-olefin addition is performed prior to theintroduction of the A -carbon-carbon double bond. Thus a16a,17a-ethylene-3-keto-A -ene is converted to its enol ether asdescribed above and this 3-ethoxy- A -diene is then treated wtih2,3-dichloro-5,6-dicyanobenzoquinone to afford the 3-keto-A -diene.Alternatively the 3-keto-A -ene may *be dehydrogenated with chloranil togive the 3-keto-A -diene.

After introduction of the 16u,17a-ethylene group, a 21-acetoxy group maybe hydrolyzed by reaction with potassium bicarbonate to afford the21-hydroxy group. The 21-hydroxy compound in turn may be treated withmethanesulfonyl chloride and the resultant 2l-mesyl compound with sodiumiodide to afford the 21-iodo intermediate which by reaction with silvermonobasic phosphate affords the 2l-ph0sphato compound.

By treatment of the 21-hydroxy compound with dihydropyran in thepresence of an acid catalyst the corresponding 21-tetrahydropyranyloxycompound is obtained. The 21-hydroxy compounds are alternativelyesterified by reaction with hydrocarbon carboxylic acyl chlorides orhydrocarbon carboxylic acids to give the ill-esters. The hydrocarboncarboxylic acyl and acyloxy groups of the present invention will containless than 12 carbon atoms and may be of a straight, branched, cyclic orcyclicaliphatic chain structure. This structure may be saturated,unsaturated, or aromatic and optionally substituted by functional groupssuch as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxycontaining up to 12 carbon atoms, nitro, amino, halogeno, and the like.Typical esters thus include acetate, propionate, enanthate, benzoate,trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate,aminoacetate, ,B-chloropropionate, adamantoate, and the like.

The substituents represented by R and R are preferably present in thestarting material or may be subsequently introduced via the conventionalprocedures. Thus an llfi-hydroxy compound is dehydrated to yield the A-ene. This is converted to the 96,1lfi-oxido compound through thebromohydrin intermediate. Treatment of the oxide with hydrogen fluorideor hydrogen chloride then yields the 9a-fluoro-l118-hydroxy or9a-chloro-ll/3- hydroxy compounds, respectively. Alternatively the A-ene is treated wtih chlorine to yield the 9a-ll,8- dichloro compound.

The A -diene system may be introduced into the molecule subsequent tothe completion of the olefin addition and those reactions involving thesubstituents R and Z Thus a 3-keto-A -ene is allowed to react with2,3-dichloro- 5,6-dicyanobenzoquin-one to afford the 3-keto-A -diene.

The following examples will tend to illustrate the present invention butare not intended to limit the scope thereof. In the naming of thel6u,l7or-ethylene derivatives it is understood that in connection withthe substituents D and E, the carbon atom attached to the C16 carbonatom of the steroid nucleus is designated as 1, and in connection withthe substituents A and B, the carbon atom attached to the C-l7 carbonatom of the steroid nucleus is designated as 2'.

EXAMPLE 1 To a solution of 5 g. of l1B,l7rx,2l-trihydroxypregn-4-ene-3,20-dione in 200 ml. of chloroform are added 40 ml. of 37%aqueous formaldehyde and 5 ml. of concentrated hydrochloric acid. Themixture is stirred for 48 hours at room temperature and the two layersthen separated. The aqueous layer is extracted with chloroform and thecombined organic layer and chloroform extracts are washed with water toneutrality, dried over sodium sulfate and evaporated to dryness to yieldllfl-hydroxy- 17,20;20,21-bis-methylenedioxypregnl-ene-3-one which isrecrystallized from methanolzether.

A mixture of 1 g. of1lfl-hydroxy-17,20;20,2l-bismethylene-dioxy-pregn-4-ene-3-one, 2 g. ofchloranil and 10 ml. of xylene is refluxed under an atmosphere ofnitrogen for 16 hours. The mixture is cooled, washed with a cold 10%sodium hydroxide solution and then with Water, dried over sodium sulfateand evaporated under reduced pressure. The residue is chromatographed onneutral alumina and further purified through recrystallization fromacetonezhexane to yield llfi-hydroxy-lZZO;20,21-bismethylenedioxypregna-4,6-dien-3-one.

T o a stirred and refluxing solution of 1 g. of l lfi-hydroxy17,20;20,2l-bismethylenedioxypregna-4,6-d-ien-3- one in 10 ml. oftriethyleneglycol dimethyl ether is added in a dropwise fashion andunder nitrogen, a 30% W./v. solution of sodium trichloroacetate. Whenthe addition of 5 equivalents of reagent fails to produce an appreciablechange in the U.V. spectrum, the addition is stopped. The solution iscooled and filtered and the filtrate is evaporated to dryness underreduced pressure. The residue thus obtained is chromatographed onalumina, eluting with methylene chloride, to yield6a,7a-dichloromethylene-11p?-hydroxy-l7,20;20,2l-bismethylenedioxypregn-4-en-3-one.

EXAMPLE 2 To a stirred and refluxing solution of l g. of llfl-hydroxy17,20;20,2l-bismethylened'ioxypregna-4,6-dien-3- one in 8 ml. ofdiethyleneglycol dimethyl ether is added in a dropwise fashion over atwo-hour period, a solution of 30 equivalents of sodiumchlorodifluoroacetate in 30 ml. of diethyleneglycol dimethyl ether. Atthe end of the reaction period, which may be followed by the U.V.spectra, the mixture is filtered and evaporated in vacuo to dryness. Theresidue is added to 10% methanolic potassium hydroxide and the mixtureis heated briefly at reflux and poured into ice water. The solid whichforms is collected, washed with water, dried and chromatographed onalumina, eluting with methylene chloride, to yield 6a,7otdifluoromethylene-l 1/8 hydroxy-17,20;20,21-bismethylenedioxypregn-4-en-3-one.

Using the procedure of Example 1 with the above modification thefollowing compounds 6-fluoro-1 1fl-hydroxy-17,20;20,2l-bismethylenedioxypregna-4,6-dien-3-one, 90cfluoroll,8hydroxy=l7,20,20,21-bismethylenedioxypreg na-4,6-dien-3-one affordedrespectively, 6,8-fluor-6a,7adifluoromethylene 11,8-hydroxy17,20;20,2)1-bismethylenedioxy pregn4-en-3-one, 90c fluoro-6a,7txdifluoromethylene1lfl-hydroxy-17,20;20,2l-bismethylenedioxypregn-4-en-3-one.

EXAMPLE 3 A solution of 0.5 g.I'm-hydroxy-17,20;20,21-bismethylene-dioxypregna-4,6-dien-3-one in ml.of dimethyl sulfoxide is added to a solution of 1 equivalent ofdimethyl- 'sulfoxonium methyl'ide in dimethylsulfoxide, prepared in themanner of Corey et al., J. Am. Chem. Soc., 87 1353 (1965). The mixtureis stirred under nitrogen and at room temperature for hours and then at50 C. for 7 hours. Fifty milliliters of water are then added and theresulting mixture extracted four times with 50 ml. of ethyl acetate. Thecombined extracts are washed with H 0 and saturated aqueous sodiumchloride solution, dried over sodium sulfate and evaporated to dryness.This residue is then chromatographed on silica, eluting with ether:methylene chloride to yield 6a,7a-methylene-1lfi-hydroxy-17,2-0;20,'21-bismethylenedioxypregn-4-en-3 -one.

EXAMPLE 4 To a solution of 1 g. of tie-hydroxy-17u,20;-20,21bismethylenedioxypregn-4-en-3-one in 75 ml. of tetrahydrofuran and 125ml. of liquid ammonia is added over a 20-minute period 0.27 g. oflithium. The mixture is refluxed with stirring for 2 /2 hours and itscolor then discharged by the careful addition of ethanol. The resultingsolution is allowed to stand at room temperature until the ammonia hasevaporated and the residue is next shaken with 100 m1. of 1:1waterzmethylene chloride. The aqueous layer is separated and extractedwith methylene chloride and the combined extracts and organic layer aredried over magnesium sulfate and evaporated. This residue is dissolvedin 1 00 ml. of 5:9 methylene chloride: acetone and titrated with 8 Nchromic acid, maintaining a temperature of C. Thirteen milliliters ofwater are then added with gentle shaking and the aqueous phase isseparated and extracted with methylene chloride. The combined extractsand organic layer are dried over magnesium sulfate and evaporated todryness to yield 11;?- hydroxy170:,20;20,21-bismethylenedioxy-5etpregnan-3- one which may be furtherpurified through recrystallization from etherzhexane.

To a stirred solution of 1 g. of l1B-hydroxy-17a,20;20,21-bismethylenedioxy-5a-pregnan-3-one and 6.6 g. of ptoluenesulfonicacid in 300 ml. of glacial acetic acid is added, over a 10 minuteperiod, a solution of 1.'1 molar equivalent of bromine and 2.45 g. ofsodium acetate in 1 10 ml. of glacial acetic acid. After stirring for anadditional 10 minute period, a solution of 75 g. of sodium acetate in150 ml. of glacial acetic acid is added and stirring is then continuedat 20 C. for 5 minutes. The reaction mixture is next poured into 1 literof ice water and solid which forms is collected and dissolved inmethylene chloride. This solution is washed with water, dilute sodiumbicarbonate solution and water, dried and evaporated to dryness. Theresidue is dissolved in 60 ml. of dimethylformamide and added to a wellstirred suspension of 12.5 g. of calcium carbonate in 440 ml. ofdimethylacetamide, heated at reflux. Refluxing is continued for 45minutes and the mixture is then filtered and concentrated to about 60ml. under reduced pressure. After the addition of 5 ml. of hexane, themixture is filtered and the filtrate is evaporated to dryness. Thisresidue is chromatographed on acid Washed alumina with a 3 :1benzenezchloroform to yield1lfl-hydroxy-l7a,20;20,211-bismethylenedioxy-5a-pregn-l-en3-one whichmay be recrystallized from cyclohexanezethyl acetate.

A solution of 45 equivalents of sodium. chlorodifluoroacetate in 50 ml.of triethylene glycol dimethyl ether is added in a dropwise fashion to arefluxing solution of 11/3- hydroxy17et,20;20,21-bismethylenedioXy-Sa-pregn-1-en- 3-one in '10 ml. oftriethylene glycol dimethyl ether. Refluxing is discontinued upon theabsence of any change in the U.V. spectra and the mixture is thenfiltered and evaporated to dryness under reduced pressure. The residueis then heated at reflux for one hour with a 1% methanolic solution ofpotassium hydroxide. At the end of this time, the reaction mixture isneutralized with dilute hydrochloric acid and evaporated to dryness. Theresidue is then chromatographed on alumina with methylene chloride toyield la,2ot difluoromethylene 11,8-hydroxy 17a,20;20,21bismethylenedioxy 5a-pregnan-3- one.

EXAMPLE 5 To a stirred and refluxing solution of l g. of llfi-hydroxy17a,20;20,21 bismethylenedioxy 50c pregn 1- en-3-one in 8 ml. ofdiethyleneglycol dimethyl ether is added in a dropwise fashion over atwo-hour period, a solution of 30 equivalents of sodiumchloridifluoroacetate in 30 ml. of diethyleneglycol dimethyl ether. Atthe end of the reaction period, which may be followed by the U.V.spectra, the mixture is filtered and evaporated in vacuo to dryness. Theresidue is added to 10% methanolic potassium hydroxide and this mixtureis heated briefly at reflux and poured into ice water. The solid whichforms is collected, washed with water, dried and chromatographed onalumina, eluting with methylene chloride, to yield 10c, 20cdiuoromcthylene 11,8 hydroxy 17,8, 20,20,21-bismethylenedioxy-5a-pregnan-3-one.

Two equivalents of bromine in 15 ml. of glacial acetic acid are addeddropwise to a solution of 1 g. of 1a,2ocdifiuoro methylene 116hydroxy-17a,20;230,21-bismethylenedioxy-Sa-pregnan-S-one in 25 ml. ofacetic acid containing a few drops of 4 N hydrogen bromide in aceticacid. After being allowed to stand for five hours at room temperature,the mixture is poured into ice water and the solid which forms iscollected by filtration, washed well with water and dried. This materialis then refluxed for 14 hours with 2 g. of sodium iodide in 40 ml. of 2-butanone, allowed to stand at room temperature for 12 hours, dilutedwith water, and extracted with ether. These extracts are washed withsodium thiosulfate solution and water and evaporated under reducedpressure. The residue is dissolved in 35 ml. of acetone, and treatedunder carbon dioxide with an aqueous solution of 11 g. of chromouschloride. After allowing the mixture to stand at room temperature for 20minutes, Water is added and the mixture is extracted with ether. Theseextracts are washed with water to neutrality, dried and evaporated. Theresidue is mixed with 0.8 g. of potassium carbonate in 35 m1. ofmethanol and 7 ml. of water and refluxed for 30 min.- utes. The mixtureis extracted with chloroform and these extracts are chromatographed onalumina With 7:3 chloroformzbenzene to yieldla,2ot-difluoromethy.lene-1l,8-hydroxy 17a,20;20,21bismethylenedioxypregn 4-en-3- one which is recrystallized fromether1hexane.

EXAMPLE 6 One gram of 6a,7ot-dichloromethylene-11,8hydroxy-17oz,20,20,21 bismethylenedioxypregn 4 en 3 one 7 in 20 ml. of 60%formic acid is heated at steam bath temperature for one hour. Themixture is cooled, diluted with water and filtered. The solid thuscollected is washed with water, dried and recrystallized from acetone:hexane to yield 6a,7a dichloromethylene11B,17ot,21-trihydroxypregn-4-ene-3,20-dione.

A mixture of 1 g. of 6a,7a-dichloromethylene-11,8,17a, 21trihydroxypregn 4 ene-3,20-dione, 4 ml. of pyridine and 2 ml. of aceticanhydride is allowed to stand at room temperature for hours. The mixtureis then poured into ice water and the solid which forms is collected byfiltration, washed with water and dried to yield 611,70dichloromethylene 115,17 dihydroxy 21- acetoxypregn-4-ene-3,ZO-dionewhich may be further purified through recrystallization fromacetonezhexane.

Using the same procedure 60,7oc-difill010l'116th3/lfiI1C-l 1;? hydroxy17,20;20,2l bismethylenedioxypregn 4 en- 3 one, 60,7a methylene 11(3hydroxy 17,20;20,21- bismetylenedioxypregn 4 en 3-one, 1a,2a-methylene11,8 hydroxy 1706,20;20,21 bismethylenedioxypregn 4 en 3 one, 1oz,2adifiuoromethylene 11/3- hydroxy 17a,20;20,21 bismethylenedioxypregn 4en- 3-one and 1a,2 x-dichloromethylene-11/3-hydroxy-17a,20;21-bismethylenedioxypregn-4-en-3-one are converted to respectively 60,7edifiuoromethylene -11fi,17tx dihydroxy 21 acetoxypregn 4 ene 3,20 dione,60,7amethylene 11,13,170: dihydroxy 21 acetoxy pregn- 4 ene 3,20 dione,1a,2a methylene 115,17 dihydroxy 21 acetoxypregn 4 ene 3,20 dione and1a,2a dichloro methylene 11fl,17a dihydroxy 21-acetoxypregn-4-ene-3,20-dione.

EXAMPLE 7 To a suspension of 1 g. of 91xfluor0-11[3,17a-dihydroxy-2l-acetoxypregn-4-ene-3,20-dioi1e in 27 ml. of methanol and 1 ml. ofwater, under nitrogen is added 1.4 g. of semicarbazide hydrochloride and0.74 g. of sodium bicarbonate. The mixture is heated at reflux for threehours and then at 45 C. for hours. The suspension is cooled and 36 ml.of water are slowly added. The solid is collected by filtration, washedwith water and dried to yield 90c fluoro 115,17a dihydroxy 21actoxypregn 4- ene-3,20-bis-semicarb azone which is recrystallized frompyridine:methanol.

A solution of 1 g. of 9a-fiuoro-11/3,17ot-dihydroxy-21-acetoxypregn-4-ene-3,20-bis-semicarbazone in 20 ml. of acetic acid and 1ml. of acetic anhydride is heated at reflux under nitrogen for 1 hour.The reaction mixture is then concentrated under reduced pressure to avolume of about 12 ml. and treated with 6 ml. of water and 3 ml. ofpyruvic acid. The mixture is allowed to stand at room tempertaure for 40hours and at 60 C. for 2 hours and is then diluted with water andextracted with chloroform. These extracts are washed with water, dilutepotassium bicarbonate solution and water, dried over magnesium sulfateand evaporated to dryness under reduced pressure. The residue ischromatographed on neutral alumina with benzene to yield9u-fiuoro-11fi-hydroxy-Zl-acetoxypregna- 4,16-diene-3,20-dione which maybe recrystallized from acetone :ether.

A mixture of 2.0 g. of9ot-fiuoro-1lfl-hydroxy-Zl-acetoxypregna-4,16-diene-3,20-dione in ml. of2-methyl-2- ethyl-1,3-dioxolane and 100 mg. of p-toluenesulfonic acid isheated for one hour. An additional 50 mg. of p-toluenesulfonic acid isadded and heated at reflux for another hour while approximately 25 ml.of 2-methyl-2-ethyl-1,3- dioxolane is removed by distillation. Themixture is then cooled, neutralized with pyridine, diluted with waterand extracted with chloroform. The extracts are washed to neutrality,dried and evaporated to dryness to yield 3,3- ethylenedioxy 90 fluoro11B hydroxy 21 acetoxypregna-4,l6-dien-20-one which is chromatographedon silica, eluted with ethyl acetatezbenzene and recrystallized frommethylene chloride.

A mixture of 2.0 g. of 3,3 cthylenedioxy 9a fluoro- 11,8 hydroxy 21acetoxypregna 4,16 dien 20- one in 140 ml. of benzene is irradiated witha 70 watt Hanan high pressure mercury vapor lamp with a Pyrex filter atroom temperature while bubbling ethylene through the solution. At theend of reaction time which may be determined by U.V. spectroscopy, thereaction mixture is evaporated in vacuo to dryness, chromatographed onsilica and the product eluted with ethyl acetate: benzene to yield3,3-ethylene-dioxy-9a-fluoro-1lfi-hydroxy 1606,170L ethylene 21acetoxy-pregn 4 en- 20-one which is recrystallized frommethanolzmethylene chloride.

A mixture of 0.5 g. of 3,3-ethylenedioxy-9a-fluoro-115- hydroxy16oc,17ot ethylene 21 acetoxypregn 4 en- 20-one in 30 ml. of acetone and50 mg. of p-toluenesultonic acid is allowed to stand at room temperaturefor 15 hours. It is then poured into ice water and extracted with ethylacetate. These extracts are washed with water to neutrality, dried oversodium sulfate and evaporated to dryness. The residue is triturated withether to yield c fluoro hydroxy 16a,17a ethylene 21-acetoxypregn-4-ene-3,20-dione which is recrystallized fromacetonezhexane.

Using the same conditions described in Example 7 the starting compoundslisted in Table 1 are transformed into those products listed in Table 2.

Table 1 60L-ChlOl'O-1 113, l7rx-dihydroxy-21-acetoxypregn-4-ene- 3,20-dione: 6a-fluoro11B,17u-dihydroxy-21-acetoxypregn-4-ene- 3,20-dione; 6a-methyl-11,8,17a-dihydroxy-21-acetoxypregn-4-ene- 3,20-dione; 900,1 lfi-dichloro-17a-hydroxy-21-acetoxypregn-4-ene- 3,20-dione; 6a-methyl-9a-fiuoro-115,17a-dihydroxy-2l-acetoxypregn-4-ene-3 ,20-dione;6u,9a-difiuoro-11,8,17ot-dihydroxy-21-acetoxypregn-4-ene- 3,20-dione;6a-chloro-9u-fluoro-11B,17a-dihydroxy2l-acetoxypregn- 4-ene-3,20-dione;6a,7a-dichloromethylene-17a-hydroxy-2l-acetoxypregn- 4-ene-3,20-dione;6a,7a-methylene-17a-hydroxy-21-acetoxypregn-4-ene- 3 ,20-dione;6a,7u-difiuoromethylene-17ot-hydroxy-2l-acetoxypregn- 4-ene-3 ,20-dione;1aim-methylene-17ot-hydroxy-2l-acetoxypregr1-4-ene- 3 ,ZO-dione; 1a,2a-difiuoromethylene-17a-hydroxy-2 1-acetoxypregn- 4-ene-3 ,2 0-dione;1 a,2 x-dichl0romethylene-17a-hydroxy-2l-acetoxypregn- 4-ene-3,20-dione;6a-flu0r0-9a,1liq-dichloro-17u-hydroxy-2l-acetoxypregn-4-ene-3,20-dione.

TABLE 2 6a-chlor0-1lfi-hydroxy-l6a,17a-ethylene-21-acetoxypregn-4-ene-3,20-dione;

6a-fluor0-11fi-hydroxy-16a,17ot-ethylene-2l-acetoxypregn-4-ene-3,20-dione;

6ot-methyl-fl-hydroxy-16a,17u-ethylene-2l-acetoxypregn-4-ene-3,20-dione-;

941,1lfi-dichloro-16a,17wethylene-21-acetoxypregn-4-ene- 3 ,20-dione;

6a-methyl-9a-fluoro-1 1B-hydroxy-16a,17a-ethylene-21-acetoxypregn-4-ene-3 ,20-dione;

6a,9a-difiuoro-l1fi-hydroxy-16m,17u-ethyleen-21-acetoxypregn-4-ene-3,20-dione;

6a,7a-dichloromethylene-16a,17ot-ethylene-2l-acetoxypregn-4-ene-3,20-dione;

When applying the above method to the starting compounds set forth belowand using the olefin indicated, there are obtained the correspondingproducts set forth below.

Starting Compound Olefin Product fia-fluoro'llfl, l7a- Allene6a-flu01'041B-hydr0xydihydroxy-Zl-aeetoxy- 16a,17a(2-methylene)pregn-4-ene-3,20-dione. ethylen e-21-acetoxypregn-4-ene-3,20-dione.6a-Chl010-11B,17cuore-11H- dihydroxy-21-acetoxypregnA-ene-3,20-dione.

6a,9a-(lifll10r0-1 18,170:-

dihydroxy-2l-acetoxypregn-4-ene-3,20-dione.

1,1'dimethoxyethylene.

6a-7a-dillu0ron1ethylene 11B,17a-dihydroxy-21- acetoxy-pregn-4-ene-3,-dione.

EXAMPLE 8 Using the same procedure and starting materials as set forthin Example 7 with one exception, namely substituting tetrafiuoroethylenefor ethylene there are obtained the corresponding16a,17ot-tetrafiuoroethylene products for those starting materials ofTable 1, namely 6a chloro 11,8 hydroxy 16a,17x tetrafluoroethylene 21acetoxypregn 4 ene 3,20 dione; 6a fluoro llfl hydroxy 160:,17octetrafluoroethylene 21- 'acetoxypregn 4 ene 3,20 dione; 6a methyl11ehydroxy 160:,1711 tetrafluoroethylene 21 acetoxypregn 4 ene 3,2'0dione; 9a,1l/3 dichloro 161x,17atetrafluoroethylene 21 acetoxypregn 4ene 3,20- dione; 60c methyl 9a fluoro 11/8 hydroxy16a,17utetrafluoroethylene 21 acetoxypregn 4 ene 3,20- dione; 9a fluoro11,6 hydroxy 160:,17u tetrafluoroethylene 21 acetoxypregn 4 ene 3,20dione; 6a, 9a difiuoro 11B hydroxy 16a,17ot tetrafluoroethylene 21acet-oxypregn 4 ene 3,20 dione; 6a chloro- 9a fluoro 115 hydroxy16a,17ot-tetrafiuoroethylene 21 acetoxypregn 4 ene 3,20-dione; 606,7(1dichloromethylene 1604,1705 tetrafiuoroethylene 21 acetoxypregn 4 ene3,20 dione; 6a,7a methylene 1604,1711- tetrafiuoroethylene 21acetoxypregn 4 ene 3,20- dione; 6:1,7u difiuoromethylene l6oc,17ottetrafluoroethylene 21 acetoxypregn 4 ene 3,20 dione; 1a, 20c methylene160:,17ot tetrafluoroethylene 21 acetoxypregn 4 ene 3,20 dione; 1a,2otdifluoromethylene 16ot,17a tetrafluoroethylene 21 acetoxypregn- 4 ene3,20 dione; 1a,2rx dichloromethylene 16a,-

l7ot tetrafluoroethylene 21 acetoxypregn 4 ene- 3,20 dione; 6a fluoro9u,11fl dichloro16ot,17atetrafiuoroethylene-Z1-acetoxypregn-4-ene-3,ZO-dione.

EXAMPLE 9 Using the same procedure and starting materials as set forthin Example 7 with one exception, namely substituting1,1-difiuoroethylene, there are obtained the corresponding16a,17a-(1,1'-difluoroethylene) products for those starting materials ofTable 1, namely EXAMPLE 10 A mixture of 1 g. of6u-methyl-11/3-hydroxy-l6ot,17aethylene-2l-acetoxypregn-4-ene-3,20-dione,2 g. of chloranil and 10 ml. of xylene is refluxed under an atmosphereof nitrogen for 16 hours. The mixture is cooled, washed with a cold 10%sodium hydroxide solution and then with water, dried over sodium sulfateand evaporated under reduced pressure. The residue is chromatographed onneutral alumina and further purified through recrystallization fromacetonezhexane to yield 6-methyl-11/8-hydroxy16a,17ot-ethylene-2lacetoxypregna-4,6-dien-3,20-dione.

Using the same procedure the following compounds 6a methyl c fluoro-1IB-hydroxy l60c,17ot ethylene- 21 acetoxypregn 4 ene 3,20 dione isconverted to 6- methyl 9oz fluoro 11/3 hydroxy l6oc,l7ot. ethylene21-acetoxypregnat,6-diene-3,20-dione.

EXAMPLE 1 1 A mixture of 0.5 g. of 6a,9u-difiuOIO-l LB-hydroxy-16a,17a-ethylene-2l-acetoxypregn-4-ene-3,20-dione, 10 ml. of dioxane and0.35 g. of 2,3-dichloro-5,6-dicyano-1,4-

benzoquinone is refluxed for 10 hours. The mixture is About 1 ml. isremoved by distillation to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for 4 days, and is then washedwith aqueous sodium carbonate solution and Water, dried and evaporated.The residue is chromatographed on neutral alumina, eluting with hexane,to yield 60,9ot-dlfll10l'O-11flhydroxy 1604,1701 ethylene 21tetrahydropyranloxypregna 1,4 diene 3,20 dione which is recrystallizedfrom pentane.

Using the same procedure the following compounds Got-fluoro 1113,21dihydroxy 1611,1711 ethylenepregna- 1,4 -diene 3,20 dione, 90c fluoro-1lfi,2l-dihydroxy 161x, 170: ethylene pregna 1,4 diene 3,20 dione areconverted to 6u-fluoro-11fi-hydroxy 1611,17 ethylene-21-tetrahydropyranyloxypregna 1,4 diene 3,20-dione, and 90: fluoro 11,6hydroxy 1611,170; ethylene 21 tetrahydropyranyloxypregna 1,4 diene 3,20dione, respectively.

EXAMPLE 15 A mixture of 1 g. of 6a-flI1OI0-1 1,5,21-dihydroxy-16a,17u-ethylenepregna-1,4-diene-3,20-dione in ml. of pyridine and 0.5g. of methanesulfonyl chloride is allowed to stand at room temperaturefor 24 hours and is then diluted with water and filtered. The solid thuscollected is dried and recrystallized from acetone:hexane to yield 60:-fluoro 1113 hydroxy16a,17a-ethylene-2l-methanesulfonyloxypregna-1,4-diene-3,20-dione.

To a stirred solution of 1 g. of above solid in 10 ml. of dry acetone isadded 1 g. of sodium iodide. The mixture is allowed to stand at roomtemperature for four hours. The precipitate is collected and evaporatedto dryness to yield 6u-fiuoro-1lfl-hydroxy-l6a,17a-ethylene-2liodopregna-l,4-diene-3,20 dione.

A mixture of 1 g. of 6a-fiuoro-11 3-hydroxy-11u,l7uethylene 21iodcpregna-1,4-diene-3,20-dione and 1.1 molar equivalents of silvermonobasic phosphate in 60 ml. of acetonitrile is heated at reflux for 2hours. The mixture is then filtered and evaporated to dryness to yield60:fluoro-1IB-hydroxy-l6a,17a-ethylene-21-phosphatopregna-l,4-diene-3,20-dionewhich may be recrystallized from methanolzethyl acetate. This product,dissolved in methanol may be triturated with aqueous sodium hydroxide toyield the corresponding monosodium and disodium salts.

EXAMPLE 16 A mixture of 1 g. of 6a-fiuoro-11,8,21-dihydroxy-16a,17a-ethylenepregna-l,4-diene-3,20dione, 4 ml. of pyridine and 2 ml.of propionic anhydride was kept at room temperature overnight and thenpoured over ice water to give 6-fiuoro-l 1,8hydroxy-16a,17a-ethylene-21-propi0- nyloxy-pregna-l,4-diene-3,20-dione.The precipitate was filtered, washed with water, dried andrecrystallized from acetonechexane.

Using the above procedure the 21-hydroxy compounds listed in Example 12are treated with acetic anhydride, propionic anhydride, caproicanhydride, enanthic anhydride and cyclopentylpropionic anhydride,respectively, to obtain the 2l-acetates, 21-propionates, 21-caproates,21- enianthates, and 21-cyclopentylpropionates.

Again using the above procedure and the SIB-hydroxy compounds preparedin Example 13 there are obtained the following 3B-acetates,3B-propionates, 3,8-caproates, S S-enanthates and3B-cyclopentylpropionates of 611,90:- difiuoro 35,11fl-dihydroxy-16a,17a-ethylene-21-acetoxypregn-4-en-3-one,60,7ot-difillOI0HlBthYl6Il6 313,1IB-dihydroxy-l6a,17a-tetrafluoroethylene-21-acetoxypregn-4 en- 20-one,10:,2ot dichloromethylene 35,11,6-dihydroxy-16a,17a-ethylene-2l-acetoxypregn-4-en-3-one, Get-fluoro- 35,11fldihydroxy 16a,17a-ethylene-21-acet0xypregn-4- en-20-one, and6a-fluoro-3fi,llp-dihydroxy-l6a,17a-tetrafiuoroethylene-Z1-acetoxypregn-4-en-20-one.

Z is a carbon-carbon single bond, a carbon-carbon double bond or thegroup bridging the C-1 and C-2 carbon atoms, wherein each of X and Y ishydrogen, chloro or fluoro;

Z is a carbon-carbon single bond, a carbon-carbon double bond or thegroup :CXY

bridging the C-6 and C-7 carbon atoms, wherein each of X and Y ishydrogen, chloro or fluoro; R is hydroxy, phosphate,tetrahydropyranyloxy or hydrocarbon carboxylic acyloxy group of lessthan 12 carbon atoms; R is hydrogen, fluoro, chloro or methyl, R beingin the S-configuration when Z is the group and R being in either the aor B-configuration when Z is a carbon-carbon single bond;

R is hydrogen, fl-hydrogen, keto or p-chloro;

R is hydrogen, fluoro or chloro, R and R beini. the

same when R is hydrogen or chloro;

R is an oxygen or the group in which R is hydrogen, tetrahydropyranyl ora hydrocarbon carboxylic acyl group of less than 12 carbon atoms;

each of A and B is hydrogen, chloro, fluoro or an alkyl group of fromone to four carbon atoms;

each of D and E is hydrogen, chloro, fluoro, an alkyl group of from oneto four carbon atoms, an alkoxy group of from one to four carbon atomsor a haloalkyl group of from one to four carbon atoms; and

A and B taken together are methylene or difluoromethylene, provided thatwhenever Z is the group ICXY that Z is a single bond or a double bond.

2. Compounds according to claim 1 wherein R is hydroxy or a hydrocarboncarboxylic acyloxy group of less than 12 carbon atoms;

R is hydrogen, fluoro or methyl;

R is hydroxy;

R is hydrogen or fluoro;

R is oxygen; and

Z and Z independent of one another, is a carboncarbon single bond or acarbon-carbon double bond; and

each of A, B, D and E is hydrogen.

3. Compound according to claim 2 wherein R is hydroxy;

R is hydrogen;

each of Z and Z is a carbon-carbon single bond.

4. Compounds according to claim 1 wherein R is hydroxy;

R is hydrogen;

R is fluoro;

Z is a carbon-carbon double bond; and

Z is a carbon-carbon single bond.

5. Compound according to claim 2 wherein R is hydroxy;

R is hydrogen; and

each of Z and Z is a carbon-carbon single bond.

6. Compound according to claim 2 wherein R is hydroxy;

R is hydrogen;

Z is carbon-carbon double bond; and

Z is carbon-carbon single bond.

7. Compound according to claim 2 wherein R is hydroxy;

each of R and R is fiuoro; and

each of Z and Z is a carbon-carbon single bond.

8. Compound according to claim 2 wherein R is hydroxy;

each of R and R is fluoro;

Z is a carbon-carbon double bond; and

Z is a carbon-carbon single bond.

9. Compound according to claim 2 wherein R is hydroxy;

R is methyl;

R is hydrogen;

Z is a carbon-carbon single bond; and

Z is a carbon-carbon double bond.

10. Compound according to claim 2 wherein R is hydroxy;

R is methyl;

R is hydrogen; and

each of Z and Z is a carbon-carbon double bond.

11. Compound according to claim 2 wherein R is hydroxy;

R is methyl;

each of Z and Z is a carbon-carbon double bond.

12. Compound according to claim 2 wherein R is hydroxy,

R is methyl;

R is fluoro;

Z is a carbon-carbon single bond; and

Z is a carbon-carbon double bond.

13. Compounds according to claim 1 wherein R is hydroxy;

R is hydrogen or fluoro;

each of R and R is chloro;

R is oxygen;

Z is a carbon-carbon single bond or double bond; and

Z is a carbon-carbon single bond;

each of A, B, D, and E is hydrogen.

14. Compound according to claim 13 wherein R is hydrogen; and

Z is a carbon-carbon single bond.

21 carbon-carbon 15. Compound according to claim 13 wherein R ishydrogen; and

Z is a carbon-carbon double bond.

16. Compound according to claim 13 wherein Z is carbon-carbon singlebond.

17. Compound according to claim 13 wherein Z is a carbon-carbon doublebond.

18. Compounds according to claim 1 wherein R is hydroxy or a hydrocarboncarboxylic acyloxy group of less than 12 carbon atoms;

R is hydrogen;

R is hydroxy;

R is hydrogen or fluoro;

R is oxygen;

Z is a carbon-carbon double bond or a carbon-carbon single bond; and

Z is the difiuoromethylene group.

19. Compounds according to claim R is hydroxy;

R is hydrogen; and

Z is the carbon-carbon single bond.

20. Compounds according to claim 18 wherein R is hydroxy;

R is hydrogen; and

Z is the carbon-carbon double bond.

21. Compounds according to claim 18 wherein R is hydroxy;

R is fluoro; and

Z is the carbon-carbon single bond.

' 22. Compounds according to claim 18 wherein R is hydroxy;

Z is the carbon-carbon double bond.

23. A compound selected from those of the formula:

18 wherein CHzOR Z j'l )jjjisr-..

3,338,928 8/1967 Beard et al.

HENRY A. FRENCH, Primary Examiner.

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,435,057 March 25 1969 John A. Zderic It is certified that error appears inthe above identified patent and that said Letters Patent are herebycorrected as shown below:

Column 4 line 26 "S ,6-dicyanobenzoquin-one should read5,6-dicyanobenzoquinone Column 6, line 43, "l7B,20;20, 21-" should read170!- ,20 ;20 ,Zl- Column 7 line 19 "bismetylenedioxypregn" should readbismethylenedioxypregn Column 8, line 64, "6a-methyl-B-hydroxy" shouldread 6a-methyl-l1B-hydroxy line 70, "ethyleen" should read ethyleneColumn 11 lines 25 to 28 cancel "la,2udifluoromethylene-l6a,l7a-ethylene-2l-acetoxypregnal,4-diene- 3,20-dione;

la,2adichloromethylene-l6a,l7a-ethylene-Zl-acetoxypregnal,4-diene-3,Z0dione;";lines 53 to 57, cancel "la,2amethylene16a,l7a-tetrafluoroethylene-2l-acetoxypregna-l,4-diene-3,20 dione;

la,2a-difluoromethylene-l6a,l7a-tetrafluoroethylene2lacetoxypregna-l,4-diene-3,20-dione;

la,2a-dichloromethylene-l6u,l7a-tetrafluoroethylene2lacetoxypregna-l,4-diene-3,20-dione;". Column 12, line 63, "16c: ,17dtetrafluoroethylene" should read l6u,l7atetra fluoroethylene line 68"4-ene-3. ZO-dione" should read 4-ene-3 ,20-dione Column 13 line 36 "11a,17a" should read 16a ,17aline 54 "6-fluoro" should read 6afluoro line63 "enianthates" should read enanthates Column 14 line 41 "ii-hydrogen"should read B-hydroxy Signed and sealed this 14th day of April 1970(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

